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Enhancing the Catalytic Deamination Activity of APOBEC3C is Insufficient to Inhibit Vif-deficient HIV-1.

Enhancing the Catalytic Deamination Activity of APOBEC3C is Insufficient to Inhibit Vif-deficient HIV-1.
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Vasudevan AA, Hofmann H, Willbold D, Häussinger D, Koenig BW, Münk C,


Vasudevan AA, Hofmann H, Willbold D, Häussinger D, Koenig BW, Münk C, (click to view)

Vasudevan AA, Hofmann H, Willbold D, Häussinger D, Koenig BW, Münk C,

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Journal of molecular biology 2017 03 15() pii 10.1016/j.jmb.2017.03.015

Abstract

The retroviral restriction factors of the APOBEC3 (A3) cytidine deaminase family catalyze the deamination of cytidines in single-stranded viral DNA. APOBEC3C (A3C) is a strong antiviral factor against viral infectivity factor (vif)-deficient simian immunodeficiency (SIV) Δvif, however, a weak inhibitor against human immunodeficiency virus (HIV)-1 for reasons unknown. The precise link between the antiretroviral effect of A3C and its catalytic activity is incompletely understood. Here we show that the S61P mutation in human A3C (A3C.S61P) boosted hypermutation in the viral genomes of SIVΔvif and murine leukemia virus but not in human immunodeficiency virus HIV-1Δvif. The enhanced antiviral activity of A3C.S61P correlated with enhanced in vitro cytidine deamination. Furthermore, the S61P mutation did not change substrate specificity of A3C, ribonucleoprotein complex formation, self-association, Zinc coordination or viral incorporation features. We propose that local structural changes induced by the serine-to-proline substitution are responsible for the gain of catalytic activity of A3C.S61P. Our results are a first step towards an understanding of A3C’s DNA binding capacity, deamination-dependent editing, and antiviral functions at the molecular level. We conclude that enhanced enzymatic activity of A3C is insufficient to restrict HIV-1, indicating an unknown escape mechanism of HIV-1.

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